Thiazide Diuretics and Fracture Risk: A Systematic Review and Meta‐Analysis of Randomized Clinical Trials

Abstract

Thiazide diuretics are commonly used antihypertensive agents. Until today, whether their use reduces fracture risk remains unclear. Our objective was to conduct a systematic review of thiazide diuretics' effects on fractures and bone mineral density (BMD) in randomized clinical trials (RCT) of adults. MEDLINE, EMBASE, CENTRAL, and the WHO's ICTRP registry were searched from inception to July 31, 2019. Two reviewers assessed studies for eligibility criteria: (i) RCTs; (ii) including adults; (iii) comparing thiazides, alone or in combination; (iv) to placebo or another medication; and (v) reporting fractures or BMD. Conference abstracts and studies comparing thiazides to antiresorptive or anabolic bone therapy were excluded. Bias was assessed using Cochrane Collaboration's Risk of Bias Tool-2. The primary outcome was fracture at any anatomical site. Secondary outcomes were osteoporotic fractures, hip fractures, and BMD at femoral neck, lumbar spine, and/or total hip. Fractures were pooled as risk ratios (RRs) using random-effect models. Prespecified subgroup analyses and post hoc sensitivity analyses were conducted. From 15,712 unique records screened, 32 trials (68,273 patients) met eligibility criteria. Thiazides were associated with decreased fractures at any site (RR = 0.87, 95% confidence interval [CI] 0.77-0.98; I 2 = 0%) and osteoporotic fractures (RR = 0.80; 95% CI 0.69-0.94; I 2 = 0%). Results were consistent in most subgroups and sensitivity analyses. Few studies reported hip fractures, and no association was found between thiazides and this outcome (RR = 0.84; 95% CI 0.67-1.04; I 2 = 0%). Only four studies reported BMD; a meta-analysis was not conducted because BMD reporting was inconsistent. Trials were deemed at low (3 studies, weight = 3%), some concerns (16 studies; 71%), or high (11 studies; 26%) risk of bias for the primary outcome. In conclusion, thiazide diuretics decreases the risk of fractures at any and at osteoporotic sites in a meta-analysis of RCTs. Additional studies are warranted in patients with high fracture risk.

Incidence and Factors Associated with Falls in Older People in a Long-Term Care Facility: A Prospective Study in Taiwan

“…The demographic characteristics in this study were similar to reports in the literature [23,24], in that the subjects were older. However, the factors associated with falls previously reported in the literature, including age [7,15], cognitive impairment [15], bodily functions [25], medications [8,9], and chronic diseases [6,7], were not significant in the present study. On the other hand, psychiatric symptoms [7] were associated with falls, as shown by the NPI score.…”

“…Conditions such as Parkinson's disease or dementia are also contributing factors, where the use of Alzheimer's medications has been associated with a reduced risk of falling [7]. Medications for cerebral circulation and diuretics have been identified as potential contributors to an increased fall risk [8,9].…”

Chronic Kidney Disease in Patients with Hip Fracture: Prevalence and Outcomes

“…NSAIDs may increase risk of acute kidney injury and/or worsening hypertension [138], the glucocorticoid induced OP/OF is common [147]. An increased fall and fracture risk was observed in users of glucocorticoids, benzodiazepines, vasodilators, antihypertensive drugs (alpha-and beta-adrenergic receptor blockers, calcium channel blockers, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blockers), loop diuretics (in contrast to thiazide diuretics [148], proton pump inhibitors and coumarin anticoagulants [139,140,[149][150][151], however, according to a recent systematic review, deprescribing drugs that increased fall-risk did not change the rate of falls [152]. Treatment of dyslipidaemia, the mainstay of CVD prevention (and decreasing the main cause of mortality), also may contribute to bone and muscle health.…”

Fall risk and cardiovascular outcomes of first‐line antihypertensive medications in nursing home residents

“…For example, thiazides (compared to RAASi) have been demonstrated to reduce the risk of fracture, with effects mediated by increased calcium absorption and gains in bone mineral density (BMD). 9 Conversely, thiazides have a propensity to cause hyponatremia, gout, and urinary urgency, 10 which could lead to a fall. A post hoc analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) trial, which randomized hypertensive patients to lisinopril, chlorthalidone, or amlodipine, found that patients using chlorthalidone had the lowest risk of fracture, 11 whereas patients using amlodipine had the greatest risk of falls initially.…”

“…Antihypertensive medications may contribute to injurious falls through their effects on bone and through effects on falls risk. For example, thiazides (compared to RAASi) have been demonstrated to reduce the risk of fracture, with effects mediated by increased calcium absorption and gains in bone mineral density (BMD) 9 . Conversely, thiazides have a propensity to cause hyponatremia, gout, and urinary urgency, 10 which could lead to a fall.…”